Reaction mass of disodium hexatitanium tridecaoxide and disodium trititanium heptaoxide

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Sodium titanates are effectively the sodium salts of the unstable titanic acid (titanium hydroxide). Titanium hydroxide is hard to isolate without rapid hydrolysis to titanium dioxide and sodium chloride. It is therefore proposed to base environmental and health assessment on these two hydrolysis products. There has been extensive research on similar substances in the ‘titanate’ grouping and these all exhibit similar behaviour in that under acid biological conditions (eg if ingested) or if dispersed in water, there is dissociation of the ions and subsequent hydrolysis / oxidation. Read-across justification for the use of TiO2 data is available in section 13.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

In this study, the NOAEL (no observed adverse effect level) of the agglomerated/aggregated TiO2 P25 (approximately 180 nm) administered at repeated doses to Sprague-Dawley (SD) rats for 28 and 90 days was observed. Ten of the 15 animals were necropsied for toxicity evaluation after the repeated-dose 90-day study, and the remaining five animals were allowed to recover for 28 days.

GLP compliance:

yes

Remarks:

approved by the Institutional Animal Care and Use Committee (IACUC) of Korea Conformity Laboratories

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Titanium dioxide

EC Number:

236-675-5

EC Name:

Titanium dioxide

Cas Number:

51745-87-0

Molecular formula:

O2Ti

IUPAC Name:

Titanium dioxide

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

TiO2 nanoparticles (AEROXIDEⓇ TiO2 P25, KRISS CRM 301–03-001, anatase/rutile (80/20), 99.9%; average primary particle size range 14–21 nm) were purchased from Evonik Industries AG (Essen, Germany). Agglomerated/aggregated TiO2 P25 (approximately 180 nm)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Pathogen-free SD rats [Crl:CD(Sprague-Dawley)] were purchased from Orient Bio Inc. (Seongnam, Korea). Healthy young adult animals (males and non-pregnant females) were acclimated and closely monitored for 6 days after arrival in the SPF animal facility area, and were randomly assigned to the control and treatment groups. Only animals with the best appearance were selected for subsequent testing. The body weights of the male and female rats were 210–232 g and 157–185 g, respectively, at the time of the first administration in the repeated-dose 28-day experiment. The body weights of the male and female rats were 185–207 g and 149–183 g, respectively, at the time of the first administration in the repeated-dose 90-day experiment. Rats were housed two per cage in an environmentally controlled room at 22.9 ± 0.5 °C and relative humidity of 54.3 ± 4.2%. The room air was replaced 10–15× per hour. Lighting was set to a 12-h light/dark cycle (on at 08 h00 and off at 20 h00).

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 5 mM sodium phosphate buffer (pH 8.0)

Details on oral exposure:

One hundred and forty healthy adult SD rats were used in this study. For the repeated-dose 28-day experiment, the animals were randomly divided into four groups, each consisting of five animals per sex. For the repeated-dose 90-day experiment, the animals were randomly assigned to four groups. Each group consisted of 10–15 animals per sex. One group was administered 5 mM sodium phosphate buffer by gavage and served as the vehicle control group (G1). The three remaining groups received one of three agglomerated/aggregated TiO2 P25 dosages by gavage (250 mg kg− 1 d− 1 (G2), 500 mg kg− 1 d− 1 (G3), and 1000 mg kg− 1 d− 1 (G4)). The dosing volume was 10 mL kg− 1 body weight. The agglomerated/aggregated TiO2 P25 were administered every morning for either 28 days or 90 days.

Frequency of treatment:

The dosing volume was 10 mL kg− 1 body weight. The agglomerated/aggregated TiO2 P25 were administered every morning for either 28 days or 90 days.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Group 1 (vehicle control)

Doses / concentrations 2

Dose / conc.:

250 mg/kg bw/day (nominal)

Remarks:

Group 2

Doses / concentrations 3

Dose / conc.:

500 mg/kg bw/day (nominal)

Remarks:

Group 3

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

Group 4

No. of animals per sex per dose:

For the repeated-dose 28-day experiment, the animals were randomly divided into four groups, each consisting of five animals per sex.
For the repeated-dose 90-day experiment, the animals were randomly assigned to four groups. Each group consisted of 10–15 animals per sex.

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Detailed clinical observations were made once on all surviving animals before the onset of administration. Functional observations were conducted during the last week of treatment for the 90-day treated study and during the last week of observation for the recovery study. Functional observations were performed within 6 h after administration. Individual animal weights were recorded at acquisition and grouping, before administration, once weekly during the study, and before necropsy. Food consumption was measured immediately before the first administration and once weekly during the study.

Sacrifice and pathology:

After administration, necropsies were conducted on all surviving animals, and complete post-mortem examinations were performed on all organs. All organs were harvested, and some organs were weighed immediately after extraction (Table S9). Excised organs were fixed in 10% neutral phosphate-buffered formalin. Testes and epididymis were fixed in Bouin’s solution, and eyes were fixed in Davidson’s solution. Bilateral organs were fixed and organs with macroscopically abnormal lesions were preserved. Thin sections were made from all the preserved organs and tissues of the vehicle control and high-dose groups, mounted on histology slides, and examined histopathologically by hematoxylin and eosin (H&E) staining.

Statistics:

Statistical differences among the vehicle control and dosing groups were analyzed by parametric or nonparametric multiple comparison methods. Differences were considered statistically significant at P < 0.05. The incidence rate was represented as a percentage.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

In the test on SD rats for 90 days. At 24 h after the last treatment, a recovery study (5 animals in each group) with a non-dose period of 28 days was performed to confirm the persistence of toxicity without treatment. No mortality or abnormal clinical signs were detected in any of the treatment groups during the exposure and recovery periods

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

effects observed, non-treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

dermal irritation

food consumption and compound intake

food efficiency

gross pathology

haematology

histopathology: neoplastic

histopathology: non-neoplastic

immunology

mortality

neuropathology

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

Target system / organ toxicity

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

1 000 mg/kg bw/day (nominal)

Any other information on results incl. tables

The NOAEL of the agglomerated/aggregated TiO2 P25 was 1000 mg/kg/d. Although there were significant differences in some results, they were unrelated to the test substance.

Applicant's summary and conclusion

Conclusions:

In this study, the subacute and subchronic oral toxicity of agglomerated/aggregated TiO2 P25 (approximately 180 nm) were investigated in rats according to the standard procedure (OECD Guidelines, No. 407 and 408) for testing chemicals.
No systemic toxicological effects were related with the agglomerated/aggregated TiO2 P25 in the repeated-dose 28-day and 90-day oral toxicity and 28-day recovery studies in SD rats under the experimental conditions used. Therefore, the NOAEL of the agglomerated/aggregated TiO2 P25 was identified as 1000 mg kg− 1 d− 1, and this test substance was not detected in the target organs.